The product of the ob gene, leptin, was reported to suppress appetite by regulating activities of the satiety centers in the brain via its receptor, termed OB-R, and to affect body weight (Friedman and Halaas, 1998). However, further studies have shown that leptin receptors are expressed in many other tissues (Cioffi et al., 1996; Emilsson et al., 1997; Hoggard et al., 1997; Glasow et al., 1998; Briscoe et al., 2001), and have suggested that leptin is involved in more diverse biological functions than expected previously.
Systematic investigations have demonstrated that serum levels of leptin are increased in obese humans as they are in various animal models of obesity (Dagogo-Jack et al., 1996). It has been reported that the OB polypeptide or “leptin” lowers both plasma insulin and glucose levels in the genetically obese ob/ob mouse (Pelleymounter et al., 1995). There has so far been no indication that mutations in the ob gene might be responsible for the frequent occurrence of obesity in humans.
U.S. Pat. No. 6,309,853 discloses OB polypeptides and fragments thereof, and their use for modulating body weight.
Non-insulin-dependent diabetes (NIDDM) or type II diabetes is caused by insulin resistance, particularly in skeletal muscle, adipose tissue and liver. Thus, despite hyperinsulinaemia, there is insufficient insulin to compensate for the insulin resistance and to maintain blood glucose in the desirable range. U.S. Pat. No. 6,399,745 discloses the use of leptin antagonists, which are fragments of human or murine leptin, for treating type II diabetes and insulin resistance in diabetic patients. US Patent Application No. 2004/0048773 discloses the use of an antagonist of leptin for treatment of disorders resulting from deficiencies in insulin secretion and of hyperglycaemia, but no specific leptin antagonist is disclosed in this application.
US Patent Application No. 2004/0072219 discloses a modified molecule having the biological activity of human leptin and being substantially non-immunogenic or less immunogenic than any non-modified molecule having the same biological activity when used in vivo. The variant leptin proteins disclosed have been designed by computer modeling, but have not been synthesized nor tested. These variants have altered T-cell epitopes, preferably by substitution of one sole amino acid, to reduce or remove immunogenic sites, while maintaining the leptin biological activity. Among the sequences disclosed are 13-mers in which the amino acid residue 39, 41 or 42 of native human leptin has been substituted with alanine.
Obesity is considered a risk for many cancers. Serum leptin levels are often elevated in obese people. Leptin acts as a mitogenic agent in many tissues; therefore, it may act to promote cancer cell growth. In fact, leptin was shown to act as a growth factor for prostate cancer cells in vitro, to induce increased migration of prostate cancer cells and expression of growth factors such as vascular endothelial growth factor (VEGF), transforming growth factor-betal (TGF-β1), and basic fibroblast growth factor (bFGF), and to enhance prostate cancer growth. (Somasundar et al., 2004; Frankenberry et al., 2004).
Besides playing an important role in the regulation of food intake and energy consumption in the brain, leptin also acts as a potential growth stimulator in normal and neoplastic breast cancer cells. It was also shown recently to induce cell proliferation in ovarian cancer cells in vitro (Choi et al., 2004).